Abstract
The present invention relates to novel 39-desmethoxyrapamycin derivatives, methods for their production, and uses thereof. In a further aspect the present invention provides for the use of these 39-desmethoxyrapamycin derivatives in the treatment of cancer and/or B-cell malignancies, the induction or maintenance of immunosuppression, the treatment of transplantation rejection, graft vs. host disease, autoimmune disorders, diseases of inflammation, vascular disease and fibrotic diseases, the stimulation of neuronal regeneration or the treatment of fungal infections.
Claims
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A compound having the formula (I):
wherein:
X represents bond or CH2;
R1 represents a keto group or (H,H);
R2 represents OH or OMe;
R3 represents H, OH or OMe;
R4 and R5 each independently represent H or OH;
R6 represents —R7, —C(O)R7, —(CH2)2—O—[CR21R22—O]a—C(O)—R23; —CR21R22—O—C(O)—R23; —POR19R20, —PO(OR19)(OR20) or Y—R15;
R7 represents —(CR8R9)m(CR10R11)pCR12R13R14;
R8 and R9 each independently represent C1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl, any of which groups may optionally be substituted with —PO(OH)2, —CF2PO(OH)2, —OH, —COOH or —NH2; or R8 and R9 each independently represent H, trifluoromethyl or F;
R10, R11, R12, R13 and R14 each independently represent C1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl, any of which groups may optionally be substituted with —PO(OH)2, —CF2PO(OH)2, —OH, —COOH or —NH2; or R10, R11, R12, R13 and R14 may be independently selected from H, —(CR8R9)qNH2, —(CR8R9)qOH, CF3, F, COOH; or R10 and R11 or R12 and R13 or R13 and R14 may be taken together with the carbon to which they are joined to form a C3-C6 cycloalkyl or a 3- to 6-membered heteroalkyl ring that contains one or more heteroatoms selected from N, O and S and that is optionally, substituted with up to 5 —(CR8R9)qOH, —(CR8R9)qNH2 or COOH groups;
Y=bond, —C(O)—O—; —(CH2)2—O—C(O)—O—;
R15 represents
R16 are each independently H or OH;
R17 is independently selected from H, OH and NH2;
R18 is independently selected from H, —CH3, —CH2OH and —COOH;
provided however that no more than 2 groups selected from R16, R17 and R18 represent H or CH3;
R19 and R20 each independently represent H or C1-C4 alkyl or R19 and R20 together represent ═CH2;
R21 is independently selected from H, CH3;
R22 is independently selected from H, —CH3, —CH═CH2, —CH2Cl, —CHCl2, —CCl3, —CH(OH)Me, —CH2OH, —CH2CH3, —CH(Cl)Me;
R23 is independently R7, Y—R15 or a 5- or 6-membered aryl or heteroaryl ring optionally substituted with between one and three groups selected from OH, F, Cl, Br, NO2 and NH2;
a represents 0 or 1;
m, p and q each independently represent an integer between 0-4;
provided however that the R7 moiety does not contain more than 12 carbon atoms and does contain at least one functional group selected from —PO(OH)2, —CF2PO(OH)2, —COOH, OH or NH2;
or a pharmaceutically acceptable salt thereof.
- A compound according to claim 1, wherein R6 is selected from the group consisting of —R7, —C(O)R7, and —(CH2)2—O—[CR21R22—O]a—C(O)—R23.
- A compound according to claim 2, wherein R23 is selected from R7 and Y—R15.
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A compound according to claim 1, wherein R7 satisfies at least one feature selected from the group consisting of:
a) R7 contains 7 or fewer carbon atoms;
b) R7 contains 5 or fewer carbon atoms;
c) R7 contains two groups selected from —PO(OH)2, —CF2PO(OH)2, —OH, —COOH and —NH2; and
d) R7 contains at least one functional group selected from —COOH, OH and NH2.
- A compound according to claim 1, wherein p, m, or both represents 0 or 1.
- A compound according to claim 1, wherein q represents 0, 1 or 2.
- A compound according to claim 1, wherein R11, R12, or both represents H.
- A compound according to claim 1, wherein R13 represents H or OH.
- A compound according to claim 1, where p represents 1, and R10 represents Me, OH or CH2OH; R11 represents Me, H or CH2OH; R11 represents Me, H or CH2OH; or both R10 and R11 represent Me, OH, or CH2OH.
- A compound according to claim 1, where m and p both represent 0; R12 and R13 both represent H and R14 represents —(CR8R9)q—OH where q=0 or 1 and R8 and R9 both represent H.
- A compound according to claim 1, where p represents 1 and m represents 0, R10 and R11 both represent H, R12 represents H, R13 represents H, OH or NH2 and R14 represents —(CR8R9)q—OH where q=0 or 1 and R8 and R9 both represent H.
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A compound according to claim 1, wherein R6 is C(O)R7;
wherein R7 is selected from —CH2OH, —C(CH2)2CH2OH, —CH(OH)—CH2OH, —CH(CH2OH)—CH2OH and —C(CH2OH)2—CH3.
- A compound according to claim 1 which is selected from the group consisting of 39-desmethoxy-40-O-[2,2-bis(hydroxymethyl)propionyl]rapamycin, 39-desmethoxy-40-O-(2-hydroxy)ethyl rapamycin, 39-desmethoxy-40-O-[2-hydroxyethyl 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate] rapamycin, 27-O-desmethyl-39-desmethoxy-40-O-[2,2-bis(hydroxymethyl)propionyl] rapamycin or a pharmaceutically acceptable salt thereof.
- A compound according to claim 1 where R6 represents —POR19R20 or —PO(OR19)(OR20).
- A compound according to claim 14 where R19 and R20 both represent CH3 or both represent CH2CH3.
- A compound according to claim 1 where R6 represents Y—R15.
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A compound according to claim 16 wherein R15 is selected from
wherein R16 and R17 are OH and R18 is CH2OH; or R16 is OH, R17 is NH2 and R18 is CH2OH; or R16 and R17 are OH and R18 is COOH; or R16 is OH, R17 is NH2 and R18 is H; or R16 is OH.
- A pharmaceutical composition comprising a compound according to claim 1, at least one pharmaceutically acceptable diluents or carriers.
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A process for preparation of a compound of formula (I) according to claim 1, which comprises:
(a) reacting a compound of formula (II):
where RA represents H or (CH2)2—OH
or a protected derivative thereof with a compound of formula (III):
HO—R6 (III);
or an activated derivative thereof
wherein the group R6 is as defined above for compounds of formula (I);
or a protected derivative thereof; or
(b) converting a compound of formula (I) or a salt thereof to another compound of formula (I) or another pharmaceutically acceptable salt thereof; or
(c) deprotecting a protected compound of formula (I).
- A composition or kit of parts comprising (i) a compound according to claim 1 and (ii) one or more other therapeutically effective agent(s).
- The composition or kit of parts of claim 20 wherein the one or more other therapeutically effective agent(s) are selected from methotrexate, leukovorin, adriamycin, prenisone, bleomycin, cyclophosphamide, 5-fluorouracil, paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, doxorubicin, tamoxifen, toremifene, megestrol acetate, anastrozole, goserelin, anti-HER2 monoclonal antibody, capecitabine, raloxifene hydrochloride, EGFR inhibitors, VEGF inhibitors, proteasome inhibitors, hsp90 inhibitors, azathioprine, corticosteroids, cyclophosphamide, cyclosporin A, FK506, Mycophenolate Mofetil, OKT-3, ATG, amphotericin B, flucytosine, echinocandins, griseofulvin, an imidazole and a triazole antifungal agent.
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A compound according to claim 16, wherein R15 is
wherein R16 is OH.
Owners (US)
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Biotica Technology Limited
(Oct 29 2007)
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Applicants
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Biotica Tech Ltd
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Inventors
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Beckmann Christoph Hendrik
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Moss Steven James
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Sheridan Rose Mary
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Zhang Mingqiang
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Wilkinson Barrie
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CPC Classifications
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C07D498/18
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IPC Classifications
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C07D498/18
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A61K31/436
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Document Preview
- Publication: Jan 19, 2010
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Application:
Mar 10, 2006
US 90825006 A
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Priority:
Mar 10, 2006
GB 2006000853 W
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Priority:
Mar 11, 2005
GB 0504994 A